Method of treating cardiac insufficiency using angiotensin-converting enzyme inhibitors

ABSTRACT

The invention relates to a method of treating cardiac insufficiency by using compounds of the formula I ##STR1## in which n is 1 or 2, R, R 1 , R 2  and R 3  are identical or different and each denote hydrogen or an organic radical and R 4  and R 5 , together with the atoms carrying them, form a mono-, bi- or tri-cyclic heterocyclic ring system. The invention furthermore relates to compounds of the formula I and agents containing these for use in the treatment of the abovementioned disease.

This is a continuation of application Ser. No. 08/445,543, filed May 22,1995, now U.S. Pat. No. 5,684,016, which is a divisional applicationSer. No. 08/359,860, filed Dec. 20, 1994, which is a divisional ofapplication Ser. No. 08/188,745, filed Jan. 31, 1994, now U.S. Pat. No.5,403,856, which is a continuation of application Ser. No. 07/920,173,filed Jul. 27, 1992, abandoned, which is a continuation of applicationSer. No. 07/636,001, filed Jan. 3, 1991, abandoned, which is acontinuation of application Ser. No. 07/313,491, filed Feb. 22, 1989,abandoned, which is a continuation of application Ser. No. 06/721,705,filed Apr. 10, 1985, abandoned.

The invention relates to a method of treating cardiac insufficiency byperoral or parenteral use of angiotensin-converting enzyme inhibitors ofthe formula I ##STR2## in which n is 1 or 2,

R denotes hydrogen,

an optionally substituted aliphatic radical with 1-8 carbon atoms,

an optionally substituted alicyclic radical with 3-9 carbon atoms,

an optionally substituted aromatic radical with 6-12 carbon atoms,

an optionally substituted araliphatic radical with 7-14 carbon atoms,

an optionally substituted alicyclic-aliphatic radical with 7-14 carbonatoms, or

a radical OR^(a) or SR^(a), in which

R^(a) represents an optionally substituted aliphatic radical with 1-4carbon atoms, an optionally substituted aromatic radical with 6-12carbon atoms or an optionally substituted heteroaromatic radical with5-12 ring atoms,

R¹ denotes hydrogen,

an optionally substituted aliphatic radical with 1-6 carbon atoms,

an optionally substituted alicyclic radical with 3-9 carbon atoms,

an optionally substituted alicyclic-aliphatic radical with 4-13 carbonatoms,

an optionally substituted aromatic radical with 6-12 carbon atoms,

an optionally substituted araliphatic radical with 7-16 carbon atoms,

an optionally substituted heteroaromatic radical with 5-12 ring atoms or

a naturally occurring α-amino acid, protected in the side chain ifnecessary,

R² and R³ are identical or different and denote hydrogen,

an optionally substituted aliphatic radical with 1-6 carbon atoms,

an optionally substituted alicyclic radical with 3-9 carbon atoms,

an optionally substituted aromatic radical with 6-12 carbon atoms or

an optionally substituted araliphatic radical with 7-16 carbon atoms and

R⁴ and R⁵, together with the atoms carrying them, form a heterocyclicmono-, bi- or tri-cyclic ring system with 5 to 15 carbon atoms.

Possible ring systems are, in particular, those of the following group:tetrahydroisoquinoline (A); decahydroisoquinoline (B); octahydroindole(C); octahydrocyclopenta b!pyrrole (D); 2-azaspiro 4.5!decane (E);2-azaspiro 4.4!nonane (F); spiro (bicyclo2.2.1!heptane)-2,3-pyrrolidine! (G); spiro (bicyclo2.2.2!octane)-2,3-pyrrolidine! (J); 2-azatricyclo 4,3,0,1⁶,9 !decane(I); decahydrocyclohepta b!pyrrole (J); octahydroisoindole (K);octahydrocyclopenta c!pyrrole (L); 2,3,3a,4,5,7a-hexahydroindole (M);2-azabicyclo 3.1.0!hexane (N); all of which can optionally besubstituted. However, the unsubstituted systems are preferred.

In the case of the compounds which possess several chiral atoms, all thepossible diastereomers, as racemates or enantiomers, or mixtures ofvarious diastereomers, are suitable.

The possible cyclic amino acid esters have the following structuralformulae: ##STR3##

A preferred embodiment comprises the use of compounds of the formula Iin which

n is 1 or 2,

R denotes hydrogen, alkyl with 1-8 carbon atoms, alkenyl with 2-6 carbonatoms, cycloalkyl with 3-9 carbon atoms, aryl with 6-12 carbon atoms,which can be mono-, di- or tri-substituted by (C₁ -C₄)-alkyl, (C₁-C₄)-alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C₁-C₄)-alkylamino, di-(C₁ -C₄)-alkylamino, (C₁ -C₄)-alkanoylamino,methylenedioxy, carboxyl, cyano and/or sulfamyl, alkoxy with 1-4 carbonatoms, aryloxy with 6-12 carbon atoms, which can be substituted asdescribed above for aryl, mono- or bi-cyclic heteroaryloxy with 5-7 or8-10 ring atoms, in which 1 or 2 ring atoms are sulfur or oxygen atomsand/or 1 to 4 ring atoms are nitrogen, which can be substituted asdescribed above for aryl, amino-(C₁ -C₄)-alkyl, (C₁-C₄)-alkanoylamino-(C₁ -C₄)-alkyl, (C₇ -C₁₃)-aroylamino-(C₁ -C₄)-alkyl,(C₁ -C₄)-alkoxy-carbonylamino-(C₁ -C₄)-alkyl, (C₆ -C₁₂)-aryl-(C₁-C₄)-alkoxycarbonylamino-(C₁ -C₄)-alkyl, (C₆ -C₁₂)-aryl-(C₁-C₄)-alkylamino-(C₁ -C₄)-alkyl, (C₁ -C₄)-alkylamino-(C₁ -C₄)-alkyl,di-(C₁ -C₄)-alkylamino-(C₁ -C₄)-alkyl, guanidino-(C₁ -C₄)-alkyl,imidazolyl, indolyl, (C₁ -C₄)-alkylthio, (C₁ -C₄)-alkylthio-(C₁-C₄)-alkyl, (C₆ -C₁₂)-arylthio-(C₁ -C₄)-alkyl, which can be substitutedin the aryl part as described above for aryl, (C₆ -C₁₂)-aryl-(C₁-C₄)-alkylthio, which can be substituted in the aryl part as describedabove for aryl, carboxy-(C₁ -C₄)-alkyl, carboxyl, carbamyl, carbamyl-(C₁-C₄)-alkyl, (C₁ -C₄)-alkoxy-carbonyl-(C₁ -C₄)-alkyl, (C₆-C₁₂)-aryloxy-(C₁ -C₄)-alkyl, which can be substituted in the aryl partas described above for aryl, or (C₆ -C₁₂)-aryl-(C₁ -C₄)-alkoxy, whichcan be substituted in the aryl part as described above for aryl,

R¹ denotes hydrogen, alkyl with 1-6 carbon atoms, alkenyl with 2-6carbon atoms, alkynyl with 2-6 carbon atoms, cycloalkyl with 3-9 carbonatoms, cycloalkenyl with 5-9 carbon atoms, (C₃ -C₉)-cycloalkyl-(C₁-C₄)-alkyl, (C₅ -C₉)-cycloalkenyl-(C₁ -C₄)-alkyl, optionally partlyhydrogenated aryl with 6-12 carbon atoms, which can be substituted asdescribed above for R, (C₆ -C₁₂)-aryl-(C₁ -C₄)-alkyl or (C₇-C₁₃)-aroyl-(C₁ or C₂)-alkyl both of which can be substituted as theabove aryl, mono- or bi-cyclic, optionally partly hydrogenatedheteroaryl with 5-7 or 8-10 ring atoms, in which 1 or 2 ring atoms aresulfur or oxygen atoms and/or 1 to 4 ring atoms are nitrogen atoms,which can be substituted as the above aryl, or the side chain, protectedif necessary, of a naturally occurring -amino acid R¹ --CH(NH₂)--COOH,R² and R³ are identical or different and denote hydrogen, alkyl with 1-6carbon atoms, alkenyl with 2-6 carbon atoms, di-(C₁ -C₄)-alkylamino-(C₁-C₄)-alkyl, (C₁ -C₅)-alkanoyloxy-(C₁ -C₄)-alkyl, (C₁-C₆)-alkoxy-carbonyloxy-(C₁ -C₄)-alkyl, (C₇ -C₁₃)-aroyloxy-(C₁-C₄)-alkyl, (C₆ -C₁₂)-aryloxycarbonyloxy(C₁ -C₄)-alkyl, aryl with 6-12carbon atoms, (C₆ -C₁₂)-aryl-(C₁ -C₄)-alkyl, (C₃ -C₉)-cycloalkyl or (C₃-C₉)-cycloalkyl-(C₁ -C₄)-alkyl and

R⁴ and R⁵ have the abovementioned meaning.

A particularly preferred embodiment comprises use of compounds of theformula I in which

n is 1 or 2,

R denotes (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl, (C₃ -C₉)-cycloalkyl,amino-(C₁ -C₄)-alkyl, (C₂ -C₅)-acylamino-(C₁ -C₄)-alkyl, (C₇-C₁₃)-aroylamino-(C₁ -C₄)-alkyl, (C₁ -C₄)-alkoxy-carbonylamino-(C₁-C₄)-alkyl, (C₆ -C₁₂)-aryl-(C₁ -C₄)-alkoxycarbonylamino-(C₁ -C₄)-alkyl,(C₆ -C₁₂)-aryl, which can be mono-, di- or tri-substituted by (C₁-C₄)-alkyl, (C₁ -C₄)-alkoxy, hydroxyl, halogen, nitro, amino, (C₁-C₄)-alkylamino, di-(C₁ -C₄)-alkylamino and/or methylenedioxy, ordenotes 3-indolyl, in particular methyl, ethyl, cyclohexyl,tert.-butoxycarbonylamino-(C₁ -C₄)-alkyl, benzoyloxycarbonylamino-(C₁-C₄)-alkyl or phenyl, which can be mono- or di-substituted by phenyl,(C₁ -C₂)-alkyl, (C₁ or C₂)-alkoxy, hydroxyl, fluorine, chlorine,bromine, amino, (C₁ -C₄)-alkylamino, di-(C₁ -C₄)alkylamino, nitro and/ormethylenedioxy, or, in the case of methoxy, can be trisubstituted,

R¹ denotes hydrogen or (C₁ -C₆)-alkyl, which can optionally besubstituted by amino, (C₁ -C₆)-acylamino or benzoylamino, (C₂-C₆)-alkenyl, (C₃ -C₉)-cycloalkyl, (C₅ -C₉)-cycloalkenyl, (C₃-C₇)-cycloalkyl-(C₁ -C₄)-alkyl, (C₆ -C₁₂)-aryl or partly hydrogenatedaryl, which can in each case be substituted by (C₁ -C₄)-alkyl, (C₁ orC₂)-alkoxy or halogen, (C₆ -C₁₂)-aryl-(C₁ to C₄)-alkyl or (C₇-C₁₃)-aroyl-(C₁ -C₂)-alkyl, both of which can be substituted in the arylradical as defined above, a mono- or bi-cyclic heterocyclic radical with5 to 7 or 8 to 10 ring atoms, in which 1 or 2 ring atoms are sulfur oroxygen atoms and/or 1 to 4 ring atoms are nitrogen atoms, or a sidechain of a naturally occurring α-amino acid, which is protected ifnecessary, but in particular hydrogen, (C₁ -C₃)-alkyl, (C₂ orC₃)-alkenyl, the side chain, protected if necessary, of lysine, benzyl,4-methoxybenzyl, 4-ethoxybenzyl, phenethyl, 4-amino-butyl orbenzoylmethyl,

R² and R³ denote identical or different radicals from the groupcomprising hydrogen, (C₁ -C₆)-alkyl, (C₂ -C₆)-alkenyl and (C₆-C₁₂)-aryl-(C₁ -C₄)-alkyl, but in particular hydrogen, (C₁ -C₄)-alkyl orbenzyl and

R⁴ and R⁵ have the abovementioned meaning.

It is particularly preferred to use compounds of the formula I in whichn is 2, R=phenyl, R¹ =methyl, R² and R³ denote identical or different(C₁ -C₆)-alkyl radicals or (C₇ -C₁₀)-aralkyl radicals, such as benzyl ornitrobenzyl, and

R⁴ and R⁵ together represent a radical of the formula ##STR4## in whichm denotes 0 or 1, p denotes 0, 1 or 2 and X denotes --CH₂ --, --CH₂--CH₂ -- or --CH═CH--, it also being possible for a 6-membered ringformed with X to be a benzene ring.

Aryl here and in the following text is preferably to be understood asoptionally substituted phenyl, bi-phenylyl or naphthyl. Correspondingstatements apply to radicals derived from aryl, such as aryloxy andarylthio. Aroyl is understood as being, in particular, benzoyl.Aliphatic radicals can be straight-chain or branched.

A monocyclic or bicyclic heterocyclic radical with 5 to 7 or 8 to 10ring atoms, 1 or 2 ring atoms of which are sulfur or oxygen atoms and/or1 to 4 ring atoms of which are nitrogen atoms, is understood as meaning,for example, thienyl, benzo b!thienyl, furyl, pyranyl, benzofuryl,pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl,indazolyl, isoindolyl, indolyl, purinyl, quinolizinyl, isoquinolinyl,phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, cinnolinyl,pteridinyl, oxyzolyl, isoxazolyl, thiazolyl or isothiazolyl. Theseradicals can also be partly or completely hydrogenated.

Naturally occurring α-amino acids are described, for example, inHouben-Weyl, Methoden der Organischen Chemie (Methods of OrganicChemistry), Volume XV/1 and XV/2.

If R¹ represents a side chain of a protected naturally occurring α-aminoacid, such as, for example, protected Ser, Thr, Asp, Asn, Glu, Gln, Arg,Lys, Hyl, Cys, Orn, Cit, Tyr, Trp, His or Hyp, groups which arecustomary in peptide chemistry are preferred as the protective groups(c.f. Houben-Weyl, Volume XV/1 and XV/2). In the case where R¹ denotesthe protected lysine side chain, the known amino-protective groups arepreferred, but especially Z, Boc or (C₁ -C₆)-alkanoyl. PossibleO-protective groups for tyrosine are, preferably, (C₁ -C₆)-alkyl, inparticular methyl or ethyl.

The following compounds can be particularly advantageously used by themethod according to the invention:

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-S-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-alanyl-S-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-lysyl-S-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid

N-(1-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl-S-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-3S-decahydroisoquinoline-3-carboxylicacid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-lysyl-(2S,3aS,7aS)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-lysyl-(2S,3aS,7aS)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-lysyl-(2S,3aS,7aS)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3-phenyl-propyl)-O-methyl-S-tyrosyl-(2S,3aS,7aS)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl-(2S,3aS,7aS)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3-(3,4-dimethylphenyl-propyl)-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylicacid

N-1-S-carbethoxy-3-(4-fluorophenyl)-propyl!-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylicacid

N-1-S-carbethoxy-3-(4-methoxyphenyl)-propyl!-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylicacid

N-1-S-carbethoxy-3-(3,4-dimethoxyphenyl)-propyl!-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3-cyclopentylpropyl)-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-(2S,3aR,7aS)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-alanyl-(2S,3aR,7aS)-octahydroindole-carboxylicacid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-lysyl-(2S,3aR,7aS)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-lysyl-(2S,3aR,7aS)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl-(2S,3aS,7aR)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-(2S,3aR,7aR)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-lysyl-(2S,3aR,7aS)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-alanyl-(2S,3aR,7aR)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-O-ethyl-S-tyrosyl-(2S,3aR,7aR)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-(2S,3aS,7aR)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl-(2S,3aS,7aS)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3,4-dimethylphenyl-propyl)-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylicacid

N-1-S-carbethoxy-3-(4-fluorophenyl)-propyl!-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylicacid

N-1-S-carbethoxy-3-(4-methoxyphenyl)-propyl!-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylicacid

N-1-S-carbethoxy-3-(3,4-dimethoxyphenyl)-propyl!-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3-cyclopentylpropyl)-S-alanyl-(2S,3aS,7aS)-octahydroindole-2-carboxylicacid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-cis-endo-2-azabicyclo3.3.0!octane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-lysyl-cis-endo-2-azabicyclo3.3.0!octane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-alanyl-cis-endo-2-azabicyclo3.3.0!octane-3-S-carboxylic acid

N-(1-S-carboxy-3-cyclohexyl-propyl)-S-alanyl-cis-endo-2-azabicyclo3.3.0!octane-3-S-carboxylic acid

N-(1-S-carbethoxy-butyl)-S-alanyl-cis-endo-2-azabicyclo3.3.0!octane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-(3,4-dimethoxyphenylpropyl)-S-alanyl-cis-endo-2-azabicyclo3.3.0!octane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-cyclopentyl-propyl)-S-alanyl-cis-endo-azabicyclo3.3.0!octane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-O-methyl-S-tyrosyl-cis-endo-2-azabicyclo3.3.0!octane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl-cis-endo-2-azabicyclo3.3.0!octane-3-S-carboxylicacid

N-(1-S-carbethoxy-3-(4-fluorophenyl-propyl)-S-alanyl-cis-endo-azabicyclo3.3.0!octane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-(4-methoxyphenyl-propyl)-S-alanyl-cis-endo-2-azabicyclo3.3.0!octane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-lysyl-(2S,3aR,6aS)-octahydrocyclopentab!pyrrole-2-carboxylic acid

N-(1-S-carbethoxy-3-cyclohexylpropyl)-lysyl-(2S,3a,6aS)-octahydrocyclopentab!pyrrole-2-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl-(2S,3aR,6aS)-octahydrocyclopentab!pyrrole-2-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-2-(2S,3aR,6aS)-octahydrocyclopentab!pyrrole-2-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-2-azaspiro4,5!decane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-O-ethyl-2-tyrosyl-azaspiro-4,5!decane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-lysyl-2-azaspiro4,5!decane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl-2-azaspiro4,5!decane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-cyclohexylpropyl)-S-lysyl-2-azaspiro4,5!decane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-2-azaspiro4,4!nonane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl-2-azaspiro4,4!nonane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-lysyl-2-azaspiro4,4!nonane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-alanyl-2-azaspiro4,4!nonane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-cyclopentyl-propyl)-S-alanyl-2-azaspiro4,4!nonane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-cyclopentyl-propyl)-S-lysyl-2-azaspiro4,4!nonane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-spiro bi-cyclo2.2.1!heptane-2,3'-pyrrolidine!-5'-S-carboxylic acid,

N-(1-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl- spiro bicyclo2.2.1!heptane-2,3'-pyrrolidine!-5'-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-lysyl-spiro bicyclo2.2.1!heptane-2,3'-pyrrolidine!-5'-S-carboxylic acid

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-alanyl-spiro bicyclo2.2.1!heptane-2,3'-pyrrolidine!-5'-S-carboxylic acid

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-lysyl-spiro bicyclo2.2.1!heptane-2,3'-pyrrolidine!-5'-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-spiro bicyclo2.2.2!octane-2,3'-pyrrolidine!-5'-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-O-ethyl-tyrosyl-spiro bicyclo2.2.2!octane-2,3'-pyrrolidine!-5'-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-lysyl-spiro bicyclo2.2.2!octane-2,3'-pyrrolidine!-5'-S-carboxylic acid

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-alanyl-spiro bicyclo2.2.2!octane-2,3'-pyrrolidine!-5'-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-2-azatricyclo 4,3,0,1⁶,9!decane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyl-2-azatricyclo4,3,0,1.sup.6,9 !decane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-lysyl-2-azatricyclo 4,3,0,1⁶,9!decane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-alanyl-2-azatricyclo 4,3,0,1⁶,9!decane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-lysyl-2-azatricyclo 4,3,0,1⁶,9!decane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-decahydrocycloheptab!pyrrole-2-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-O-ethyl-S-tyrosyldecahydrocycloheptab!pyrrole-2-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-lysyl-decahydrocycloheptab!pyrrole-2-S-carboxylic acid

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-alanyl-decahydrocycloheptab!pyrrole-2-S-carboxylic acid

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-lysyl-decahydrocycloheptab!pyrrole-2-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-trans-octahydroisoindole-1-S-carboxylicacid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-cis-octahydroisoindole-1-S-carboxylicacid

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-alanyl-transoctahydroisoindole-1-S-carboxylicacid

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-alanyl-cis-octahydroisoindole-1-S-carboxylicacid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-cis-octahydrocyclopentab!pyrrole-1-S-carboxylic acid

benzylN-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-alanyl-cis-octahydrocyclopentac!pyrrole-1-S-carboxylate

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-lysyl-cis-octahydrocyclopentac!pyrrole-1-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-2,3,3a,4,5,7a-hexahydroindole-cis-endo-2-S-carboxylicacid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-lysyl-2,3,3a,4,5,7a-hexahydroindole-cis-endo-2-S-carboxylicacid

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-lysyl-2-azabi-cyclo3.1.0!hexane-3-S-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-lysyl-2-azabicyclo3.1.0!hexane-cis-endo-3-S-carboxylic acid

N-(1-S-carbethoxy-3-cyclopentylpropyl)-S-alanyl-2-azabicyclo3.1.0!hexane-3-carboxylic acid

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-cis-endo-2-azabicyclo3.1.0!hexane-3-S-carboxylic acid and

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-alanyl-cis-endo-2-azabicyclo3.1.0!hexane-3-S-carboxylic acid.

These compounds can be prepared, for example, by the process describedin German Patent Application P 33 33 455.2, by converting thetert.-butyl or benzyl radicals described in the Application into themonocarboxylic acid derivatives in a known manner by acid or alkalinehydrolysis or by hydrogenolysis catalyzed by a noble metal. The Nε-benzyloxycarbonyl protective group of the lysine derivatives isremoved by hydrogenolysis catalyzed by a noble metal. The abovementionedcompounds can easily be converted into the corresponding salts (forexample hydrochlorides, maleates, fumarates and the like) withphysiologically acceptable acids or bases (in the case of mono- ordi-carboxylic acids), and can be used according to the invention in theform of the salts.

The compounds of the formula I are inhibitors of angiotensin-convertingenzyme (ACE) or intermediates in the preparation of such inhibitors andcan also be employed for combating hypertension of various origins. Thecompounds of the formula I are known from German Offenlegungsschrift3,211,397, German Offenlegungsschrift 3,227,055, European PatentApplication 46,953, European Patent Application 79,022, European PatentApplication 84,164, European Patent Application 89,637 and EuropeanPatent Application 90,362. They are furthermore the subject of GermanPatent Applications P 32 42 151.6, P 32 46 503.3, P 32 46 757.5, P 33 00774.8 and P 33 24 263.1.

In carrying out the method according to the invention, theangiotensin-converting enzyme inhibitors described above can be used onmammals, such as monkeys, dogs, cats, rats, humans and the like. Thecompounds suitable for the use according to the invention areadvantageously incorporated into pharmaceutical products in the usualmanner. They can be converted into the customary administration forms,such as capsules, tablets, coated tablets, solutions, ointments andemulsions and also into depot form. If appropriate, the active compoundcan also be in microencapsulated form. The products can containacceptable organic or inorganic concomitant substances, for examplegranulating substances, adhesives and binders, lubricants, suspendingagents, solvents, antibacterial agents, wetting agents andpreservatives. Oral and parenteral use forms are preferred. Thecompounds of the formula I can be administered in dosages of 0.1-50 mgper dose once to three times daily.

The efficacy of the compounds of the formula I in various forms ofcardiac insufficiency can be derived from their action in various testmodels. The results withN-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-cis-endo-2-azabicyclo3,3,0!octane-3-S-carboxylic acid (formula II) may in each case serve asexamples below. ##STR5##

It is known that converting enzyme inhibitors are capable of inhibitingthe enzyme not only in the serum but also in various tissues, andespecially also in the heart. This inhibition in cardiac tissue reducesthe formation of angiotensin II and hence its adverse influences onvarious parameters of heart action.

Oral treatment of spontaneously hypertensive rats with a single dose of1 mg/kg significantly inhibits the ACE in the heart for longer than 24hours. In contrast, with 30 mg/kg ofN-(1-carbethoxy-3-phenyl-propyl)-S-alanyl-S-proline (enalapril)perorally, already no further significant inhibition is observed aftermore than 6 hours. Chronic oral treatment of spontaneously hypertensiverats for two weeks with 1 mg/kg of the compound of the formula II leadsto a 55% inhibition of the ACE in the heart at the end of treatment,whilst with 30 mg/kg of enalapril perorally no inhibition is observed,under otherwise identical conditions. In addition, the systemic loweringof blood pressure caused by compounds of the formula I leads to areduction in the after-load and hence to relief of the incompetentheart.

Postganglionic sympathetic stimulation on the isolated heart leads, viaincreased catecholamine release, to an increase in heart rate andcontractility and to a decrease in coronary blood flow. Oralpretreatment with 1 mg/kg perorally of the compound of the formula I inrabbits significantly reduces the influence on heart rate and coronaryblood flow, but leaves the contractility unaffected. These effects acttogether to protect the incompetent heart.

Angiotensin I decreases whilst bradykinin increases the coronary bloodflow in the isolated heart of rabbits, guineapigs and rats. Oralpretreatment of the animals with 1 mg/kg of the compound of the formulaI perorally significantly reduces the effect of angiotensin I andincreases the action of bradykinin. The same effect can only be achievedwith 30 mg/kg of enalapril.

The following examples show the use forms for the treatment of cardiacinsufficiency by the method according to the invention. The compounds ofthe formula I can be converted into the corresponding use formsanalogously to the examples.

EXAMPLE 1

Preparation of the agent used according to the invention for oraladministration in the treatment of cardiac insufficiency.

1,000 tablets each containing 10 mg of1-N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo3.3.0!octane-3-carboxylic acid are prepared with the followingauxiliaries:

    ______________________________________                                        N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-                                                            10     g                                            1S,3S,5S-2-azabicyclo 3.3.0!octane-3-                                         carboxylic acid                                                               corn starch               140    g                                            gelatin                   7.5    g                                            microcrystalline cellulose                                                                              2.5    g                                            magnesium stearate        2.5    g                                            ______________________________________                                    

The N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo3.3.0!octane-3-carboxylic acid and corn starch are mixed with an aqueousgelatin solution. The mixture is dried and ground to granules.Microcrystalline cellulose and magnesium stearate are mixed with thegranules. The granules formed are compressed to form 1,000 tablets, eachtablet containing 10 mg of the ACE inhibitor.

These tablets can be used for the treatment of cardiac insufficiency.

EXAMPLE 2

1,000 tablets each containing 10 mg ofN-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-(2S,3aR,7aS)-octahydroindole-2-carboxylicacid hydrochloride are produced analogously to Example 1.

EXAMPLE 3

Gelatin capsules each containing 10 mg ofN-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo3.3.0!octane-3-carboxylic acid are filled with the following mixture:

    ______________________________________                                        N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-                                                            10     mg                                           1S,3S,5S-2-azabicyclo 3.3.0!octane-3-                                         carboxylic acid                                                               magnesium stearate        1      mg                                           lactose                   214    mg                                           ______________________________________                                    

These capsules can be used for the treatment of cardiac insufficiency.

EXAMPLE 4

The preparation of an injection solution for the treatment of cardiacinsufficiency is described below:

    ______________________________________                                        N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-                                                            250    mg                                           1S,3S,5S-2-azabicyclo 3.3.0!octane-3-                                         carboxylic acid                                                               methylparaben             5      g                                            propylparaben             1      g                                            sodium chloride           25     g                                            water for injection purposes                                                                            5      l                                            ______________________________________                                    

The N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo3.3.0!octane-3-carboxylic acid, preservatives and sodium chloride aredissolved in 3 L of water for injection purposes and the solution ismade up to 5 1 with water for injection purposes. The solution issterile-filtered and filled aseptically into pre-sterilized bottles,which are closed with sterilized rubber caps. Each bottle contains 5 mlof solution.

EXAMPLE 5

Tablets which can be used for the treatment of cardiac insufficiency areprepared as in Example 1, with the difference that instead ofN-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo3.3.0!-octane-3S-carboxylic acid,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo3.3.0!octane-3-carboxylic acid or

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-2S,3aR,7aS-octahydroindole-2-carboxylicacid orN-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-cis-2,3,3a,-4,5,7a-hexahydror1H!indole-2-S-endo-carboxylicacid orN-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-cis-2,3,4a,4,5,7a-hexahydro1H!indole-2S-endo-carboxylic acid or

N-(1-S-carboxy-3-phenyl-propyl)-S-lysyl-1S,3S,5S-2-azabicyclo-3.3.0!octane-3-carboxylic acid or

N-(1-S-carbethoxy-3-cyclohexyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo3.3.0!-octane-3-carboxylic acid or

N-(1-S-carboxy-3-cyclohexyl-propyl)-S-lysyl-1S-3S,5S-2-azabicyclo3.3.0!octane-3-carboxylic acid is used.

EXAMPLE 6

An injection solution is prepared analogously to the instructions givenin Example 4, with the difference that instead ofN-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo3.3.0!octane-3-carboxylic acid,

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-1S,3S,5S-2-azabicyclo3.3.0!octane-3-carboxylic acid or

N-(1-S-carbethoxy-3-phenyl-propyl)-S-alanyl-2S,3aR,7aS-octa-hydroindole-2-carboxylicacid hydrochloride or

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-2S,3aR,7aS-octahydro-indole-2-carboxylicacid or

N-(1-S-carbethoxy-3-cyclo-hexyl-propyl)-S-alanyl-cis-2,3,3a,4,5,7a-hexahydro1H!-indole-2-S-endo-carboxylic acid or

N-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-cis-2,3,3a,4,5,7a-hexahydro1H!-indole-2-S-endo-carboxylic acid or

N-(1-carboxy-3-phenyl-propyl)-S-lysyl-1S,3S,5-2-azabicyclo3.3.0!octane-3-carboxylic acid or

N-(1-S-carbethoxy-3-cyclohexyl)-S-alanyl-1S,3S,5S-2-azabicyclo3.3.0!octane-3-carboxylic acid or

N-(1-S-carboxy-3-cyclohexyl-propyl)-S-lysyl-1S,3S,5S-2-azabicyclo3.3.0!octane-3-carboxylic acid is used.

We claim:
 1. A method for treating cardiac insufficiency in a mammalcomprising the step of administering to a mammal in recognized need of,and for the purpose of said treatment, an amount of anangiotensin-converting enzyme inhibitor effective for said treatment,said angiotensin-converting enzyme inhibitor having the formula I:##STR6## in which R is hydrogen, methyl, ethyl or benzyl; or apharmaceutically acceptable salt thereof.
 2. A method of treatingcardiac insufficiency in a mammal comprising the step of administeringto a mammal in recognized need of, and for the purpose of saidtreatment, an amount of angiotensin-converting enzyme inhibitoreffective for said treatment, said angiotensin-converting enzymeinhibitor beingN-(1-S-carboxy-3-phenyl-propyl)-S-alanyl-S-1,2,3,4-tetrahydroisoquinoline-3-carboxylicacid or a pharmaceutically acceptable salt thereof.
 3. The methodaccording to claim 1, wherein said inhibitor or salt thereof isadministered orally or parenterally.